Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE

Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.

Signal Transduction*; Liver Cirrhosis/*pathology ; Liver Regeneration/*physiology ; Receptors, CXCR/*metabolism ; Receptors, CXCR4/*metabolism; Acute Disease ; Animals ; Bile Ducts/surgery ; Carbon Tetrachloride ; Chemical and Drug Induced Liver Injury, Chronic/metabolism ; Chemical and Drug Induced Liver Injury, Chronic/pathology ; Chemokine CXCL12/metabolism ; Chronic Disease ; Disease Models, Animal ; Endothelial Cells/cytology ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Ligation ; Mice ; Receptor, Fibroblast Growth Factor, Type 1/metabolism

Chemical or traumatic damage to the liver is frequently associated with aberrant healing (fibrosis) that overrides liver regeneration. The mechanism by which hepatic niche cells differentially modulate regeneration and fibrosis during liver repair remains to be defined. Hepatic vascular niche predominantly represented by liver sinusoidal endothelial cells deploys paracrine trophogens, known as angiocrine factors, to stimulate regeneration. Nevertheless, it is not known how pro-regenerative angiocrine signals from liver sinusoidal endothelial cells is subverted to promote fibrosis. Here, by combining an inducible endothelial-cell-specific mouse gene deletion strategy and complementary models of acute and chronic liver injury, we show that divergent angiocrine signals from liver sinusoidal endothelial cells stimulate regeneration after immediate injury and provoke fibrosis after chronic insult. The pro-fibrotic transition of vascular niche results from differential expression of stromal-derived factor-1 receptors, CXCR7 and CXCR4 (refs 18, 19, 20, 21), in liver sinusoidal endothelial cells. After acute injury, CXCR7 upregulation in liver sinusoidal endothelial cells acts with CXCR4 to induce transcription factor Id1, deploying pro-regenerative angiocrine factors and triggering regeneration. Inducible deletion of Cxcr7 in sinusoidal endothelial cells (Cxcr7(iΔEC/iΔEC)) from the adult mouse liver impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors. By contrast, after chronic injury inflicted by iterative hepatotoxin (carbon tetrachloride) injection and bile duct ligation, constitutive FGFR1 signalling in liver sinusoidal endothelial cells counterbalanced CXCR7-dependent pro-regenerative response and augmented CXCR4 expression. This predominance of CXCR4 over CXCR7 expression shifted angiocrine response of liver sinusoidal endothelial cells, stimulating proliferation of desmin(+) hepatic stellate-like cells and enforcing a pro-fibrotic vascular niche. Endothelial-cell-specific ablation of either Fgfr1 (Fgfr1(iΔEC/iΔEC)) or Cxcr4 (Cxcr4(iΔEC/iΔEC)) in mice restored the pro-regenerative pathway and prevented FGFR1-mediated maladaptive subversion of angiocrine factors. Similarly, selective CXCR7 activation in liver sinusoidal endothelial cells abrogated fibrogenesis. Thus, we demonstrate that in response to liver injury, differential recruitment of pro-regenerative CXCR7-Id1 versus pro-fibrotic FGFR1-CXCR4 angiocrine pathways in vascular niche balances regeneration and fibrosis. These results provide a therapeutic roadmap to achieve hepatic regeneration without provoking fibrosis.

Comment in: Hepatology. 2014 Aug;60(2):754-6. (PMID: 24615996)

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United States HHMI Howard Hughes Medical Institute; R01HL097797 United States HL NHLBI NIH HHS; U54CA163167 United States CA NCI NIH HHS; R01 HL097797 United States HL NHLBI NIH HHS; R01 HL119872 United States HL NHLBI NIH HHS; RC2 HL101846 United States HL NHLBI NIH HHS; R01 HL053793 United States HL NHLBI NIH HHS; RC2HL101846 United States HL NHLBI NIH HHS; R01 DK095039 United States DK NIDDK NIH HHS; R01HL119872 United States HL NHLBI NIH HHS; R01DK095039 United States DK NIDDK NIH HHS

0 (CXCR4 protein, mouse)
0 (Chemokine CXCL12)
0 (Cmkor1 protein, mouse)
0 (Cxcl12 protein, mouse)
0 (Receptors, CXCR)
0 (Receptors, CXCR4)
CL2T97X0V0 (Carbon Tetrachloride)
EC 2.7.10.1 (Fgfr1 protein, mouse)
EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1)

Date Created: 20131122 Date Completed: 20140128 Latest Revision: 20211021

20221213

PMC4142699

10.1038/nature12681

24256728